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M a ria d e L o u rd e s L o p e s F e rra ri C h a u ffa ille , M ih o k o Y a m a m o to , V ic e n te O d o n e F ilh o , M a ria T h e re z a A lm e id a , P a u lo M a lu f J r., L ilia n M .C ris to fa n i, J o s e K e rb a u y , S u z a n a C .R a im o n d i
A
t (9;11) translocation in childhood acute mixed leukemia
D e p a r t m e n t o f H e m a t o l o g y , E s c o l a P a u l i s t a d e M e d i c i n a - S i l o P a u l o , S p , B r a z i l I n s t i t u t o d a C r i a n f a , U n i v e r s i d a d e d e S i l o P a u l o - S i l o P a u l o , S p , B r a z i l C y t o g e n e t i c L a b o r a t o r y , S t . J u d e C h i l d r e n ' s R e s e a r c h H o s p i t a l - M e m p h i s , T e l l l l . , U S A
W e present the case of a child w ith acute lym phoid leukem ia (A LL) w ho w as m orphologically classified as FA B L 1 (P A S and peroxi-dase w ere negative). R em ission w as achieved w ith an A LL-type protocol (G B TLI). Five m onths after the discontinuation of therapy, the patient presented m ixed leukem ia (C 01O , C 019, C 013 and C 033 w ere positive) w ith t (9;11) (p21 ;q23) translocation. U nfortu-nately, as cytogenetic and im m unophenotype studies w ere not perform ed at diagnosis, tw o possibilities could be considered for the relapse; secondary m ixed leukem ia w ith clonal chrom osom e changes, or m ixed leukem ia from the beginning.
U N ITE R M O S : Leukem ia, karyotipe. E pipodophillotoxin derivative.
C A S E R E P O R T
A
nw ith8 y e a r-o ldth e fo llo w in gb o y w a sre a d in g s :firs t s e e nH g =in A u g u s t9 .5 g p e rc e n t,1 9 8 9W B C = I 8 5 ,0 0 0 /m m3
w ith 9 0 p e rc e n t b la s ts a n d
p la te le t c o u n t= 3 0 ,0 0 0 /m m3
• A b o n e m a rro w a s p ira tio n
re v e a le d ly m p h o b la s t re p la c e m e n ts th a t w e re n e g a tiv e fo r
m y e lo p e ro x id a s e a n d P A S s ta in s . N o im m u n o p h e n o ty p in g
o r c y to g e n e tic s w a s p e rfo rm e d . T h e m o rp h o lo g ic a l
d ia g n o s is o f A L L , L 1 b y F A B c rite rial
w a s m a d e , a n d th e
c h ild w a s tre a te d a c c o rd in g to th e A L L -8 5 p ro to c o l o f th e
B ra z ilia n C o o p e ra tiv e G ro u p fo r th e T re a tm e n t o f A c u te
A d d re s s fo r c o rre s p o n d e n c e :
M a ria d e L o u rd e s L o p e s F e rra ri C h a u ffa ille ,M D
D is c ip lin a d e H e m a to lo g ia - E s c o la P a u lis ta d e M e d ic in a R u a B o tu c a tu , 7 4 0 -3Qa n d a r - V I. C le m e n tin o
S a o P a u lo / S P -B ra s il - C E P 0 4 0 2 3 -9 0 0
L e u k e m ia , w h ic h c o n s is ts o f: I) in d u c tio n w ith V in c ris tin e ,
D e x a m e th a s o n e , D a u n o m y c in , L -a s p a ra g in a s e a n d
C y to s in e A ra b in o s id e ; 2 ) in te n s ific a tio n w ith E to p o s id e
(e p ip o d o p h y llo to x in d e riv a tiv e ) a n d C y to s in e A ra b in o s id e
a n d : 3 ) m a in te n a n c e w ith a ro ta tio n o f th e fo llo w in g d ru g
p a irs fo r 1 2 3 w e e k s : D e x a m e th a s o n e a n d E to p o s id e ;
T e n ip o s id e a n d C y to s in e A ra b in o s id e ; a n d 6
-M e rc a p to p u rin e a n d M e th o tre x a te . C e n tra l n e rv o u s s y s te m
p ro p h y la x is c o n s is te d o f c ra n ia l irra d ia tio n (2 4 G y ) a n d
tri p Ie in tra th e c a l th e ra p y . 2
F iv e m o n th s a fte r tre a tm e n t w a s c o m p le te d , a
b o n e m a rro w re la p s e o c c u rre d . A t th a t tim e , b o n e
m a rro w a s p ira te s h o w e d 8 0 p e rc e n t m y e lo b la s ts .
M y e lo p e ro x id a s e a n d S u d a n B la c k B w e re n e g a tiv e ,
P A S w a s 3 9 p e rc e n t p o s itiv e a n d d iffu s e ly g ra n u la r,
a lp h a n a p h ty l a c e ta te e s te ra s e w a s 5 5 p e rc e n t p o s itiv e
w ith o u t b e in g in h ib ite d b y N a F , a n d A S D e s te ra s e w a s
n e g a tiv e . T h e im m u n o p h e n o ty p e w a s d e te rm in e d o n
b o n e m a rro w c e lls b y p e rfo rm in g th e s ta n d a rd m e th o d
C H A U FFA ILLE , M .L.L.F.; Y A M A M O TO , M .; O O O N E Fo, V . et al. - A t (9;11) translocation in childhood acute m ixed leukem ia
1128
of indirect im m unofluorescence4 using the follow ing panel of m onoclonal antibodies w ith the respective results: C D 33 (M y9)
=
24 percent, C D 13 (M y7)=
22 percent, C D 14 (M y 4) <5 percent, C D 19 (B 4)=
35 percent, C D 10 (calla) = 37 percent, C D 7 (leu 9) = 12 percent, C D 41 (pltl) <2 percent, and sIg=
11 percent. R esults greater than 20 percent w ere considered positive. In addition, stained im m unophenotyping on bone m arrow sm ears w as perform ed by the alkaline phos phatase/anti -al kal i ne phos ph atase tech n i que (A PA A P), confirm ing previous results of m onoclonal antibodies.6 C hrom osom e studies w ere perform ed onbone m arrow cells exam ined after 24 hours of unstim ulated culture at 37°C using standard techniques. I I I T he chrom osom es w ere classified
according to ISC N .s R esults w ere: 46,X Y , t(9; 11) (p21;q23) (14 cells)/45,X Y , t(9;11) (p21;q23),-13 (6 cells)/ 46,X Y (2 cells).
T he patient w as placed on a new therapeutic regim en, once again achieving a com plete rem ission that lasted for 5 m onths, w hen a m arrow relapse occurred.
D IS C U S S IO N
cytogenetically distinct from classical therapy related to m yelodysplastic syndrom es and A M L .14 O ther authors confirm that this rearrangem ent is a non-random cytogenetic abnorm ality of therapy-related A M L .17.IO .lJ.20.19
A round 8 percent of the children treated for A L L develop secondary leukem ia 5 to 36 m onths after treatm ent, II and 9 out of 91 secondary A M L cases studied by PE R D E R SE N -B JE R G A A R D et al.1 o show ed
rearrangem ent of (11 q23). T he latency for developm ent of secondary leukem ia w as shorter w hen com pared to patients w ithout abnorm alities of chrom osom e I I .
T he cum ulative risk of secondary A M L is apparently increased am ong certain groups, especially those w ith a T -cell phenotype (19.1 percent at 6 years)11 and those w ho received epipodophyllotoxins once or tw ice a w eek (12 percent at 6 years)Y It seem s that it is the treatm ent frequency, and not the leukem ia cell phenotype, that is critical in influencing the risk of secondary A M L arising during rem ission of A L L Y Im m unophenotypic studies in the present case revealed that blast cells expressed early pre-B and m yeloid m arkers.
U nfortunately, as cytogenetics and im m unophenotype studies w ere not perform ed at diagnosis, w e cannot affirm w hat happened in relapse. W e could consider the possibility of a secondary m ixed leukem ia w ith clonal chrom osom e changes of t(9: 11) (p21 :q23). if w e interpret the initial
F ig u re 1 - B o n e m a rro w k a ry o ty p e s h o w in g 4 5 ,X Y , t(9 ; 1 1 )(p 2 1 ; q 2 3 ), -1 3 . 12 18 x y 17 4 10 22 18 21 3 8 15 20 7 2 14 19 8 1 13 T ranslocations involving (11q23) are
com m on in acute m yeloid leukem ia (A M L ) of the M 5 FA B subtype. 15 T he t (9; 11) (p21 ;q23) translocation has been associated w ith characteristic clinical features, and is a superior treatm ent outcom e for previously untreated pediatric A M L .'7.'3.7 A lthough rare, this translocation has also been seen in new ly diagnosed A L L . IIIt has been speculated that acute
cases of leukem ia associated w ith abnorm alities of (11 q23) originate from a m ultipotential stem cell that is capable of differentiating along m yeloid or lym phoid pathw ays,'S
A (11 q23) translocation w as found to have relapsed in several cases of com m on pre-B A L L that had either converted to calla negative pre-B A L L or A N L L .12 A uthors have suggested the possibility of the em ergence of the pluripotent stem cell follow ing chem otheraputic eradication of the original B -cell precursor line.'6
M ore recently, at (9;I I )translocation has been described in A M L secondary to acute lym phoid leukem ia previously treated w ith epipodo-phyllotoxins, etoposide and teniposide.II.IO .14T his syndrom e is clinically, pathologically and
1129
m o rp h o lo g y a n d p ro lo n g e d first re m issio n w ith a n A L L -ty p e
p ro to c o l a s a c o m m o n ly -se e n c h ild h o o d A L L . P re v io u s
e x p o su re to d ru g s, p a rtic u la rly e p y p o d o p h y llo to x in s, 1 0c o u ld
su g g e st th a t th e a c u te le u k e m ia w a s d ru g in d u c e d , a lth o u g h
a se c o n d p rim a ry le u k e m ia in a p re v io u sly m ix e d c a se c a n n o t
b e e x c lu d e d .3 P e rh a p s c h e m o th e ra p y c h a n g e d th e o rig in a l
c lo n e b y a lte rin g its p h e n o ty p ic e x p re ssio n . W f? c o u ld a lso
c o n sid e r th e c a se a s b e in g a m ix e d le u k e m ia fro m th e
b e g in n in g w h ic h re m itte d a n d , a fte r d isc o n tin u a tio n o f
th e ra p y , h a d a la te r re la p se .
N o tw ith sta n d in g th e la c k o f im m u n o p h e n o ty p e a n d
c y to g e n e tic stu d ie s a t d ia g n o sis, w e w o u ld lik e to a le rt
. h e m a to lo g ists th a t in te n siv e c h e m o th e ra p y m a y b e a lso c a p a b le o f in d u c in g se c o n d a ry o r tre a tm e n t-re la te d
le u k e m ia in c h ild re n . T h is o u g h t to b e a c o n c e rn h e re in
B ra z il, a s it is in th e re st o f th e w o rld .
RESUMO
A p re se n ta m o s 0 c a so d e u m a c ria n 9 a c o m le u c e m ia a g u d a c 1 a ssific a d a m o rfo lo g ic a m e n te c o m o L L A (le u c e m ia lin f6 id e a g u d a ) F A B L 1 (P A S e p e ro x id a se n e g a tiv o s) q u e a lc a n 9 0 u re m issa o c o m p ro to c o lo p a ra L L A (G B T L I). A p 6 s c in c o m e se s fo ra d e te ra p ia d e se n v o lv e u u m a le u c e m ia m ista (C 0 1 O , C 0 1 9 , C 0 1 3 e C 0 3 3 p o sitiv o s) c o m tra n slo c a 9 a o t(9 ; 1 1 )(p 2 1 ;q 2 3 ). C o m o , in fe liz m e n te , o s e stu d o s d e c ito g e n e tic a e im u n o fe n o tip a g e m n a o fo ra m re a liz a d o s a o d ia g n 6 stic o , p o d e -se c o n sid e ra r d u a s p o ssib ilid a d e s p a ra a re c a fd a : u m a le u c e m ia m ista se c u n d a ria c o m a lte ra 9 a o c ro m o sso m ic a c lo n a l o u u m a le u c e m ia m ista d e sd e 0 in fc io .
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1130
1 1 . P u i C h , B e h m F G , R a im o n d i S C , e t a l. S e c o n d a ry a c u te
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1 9 8 9 ;3 2 1 : 1 3 6 -4 2 .
1 2 . P u i C h , R a im o n d i S C , B e h m F G , e t a l. S h ifts in b la s t c e ll
p h e n o ty p e a n d k a ry o ty p e a t re la p s e o f c h i Id h o o d
ly m p h o b la s tic le k e m ia . B lo o d 1 9 8 6 ;6 8 : 1 3 0 6 -1 0 .
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le u k e m ia s e c o n d a ry to in h ib ito rs o f to p o is o m e ra s e II;
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(2 ):1 0 7 -1 1 .
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d e n o v o a n d s e c o n d a ry a c u te m y e lo b la s tic le u k e m ia .
L e u k e m ia 1 9 9 2 ;6 (6 ):5 1 3 -9 .
1 8 . S e a b rig h t M A . A ra p id b a n d in g te c h n iq u e fo r h u m a n
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-re la te d le u k e m ia : Id e n tific a tio n o f a n e w s u b s e t o f
s e c o n d a ry le u k e m ia . C a n c e r 1 9 9 0 ;6 8 :6 0 0 -4 .
2 0 . W in ic k N J , M c k e n n a R W , S h u s te r 1 1 ,e t a l. S e c o n d a ry a c u te
m y e lo id le u k e m ia in c h ild re n w ith a c u te ly m p h o b la s tic
le u k e m ia tre a te d w ith e to p o s id e . J o u rn C lin O n c o l
1 9 9 3 ; 1 1 (2 ):2 0 9 -1 7 .
S a o P a u lo M e d ic a l J o u rn a l/R P M 1 1 4 (2 ): 1 1 2 7 -1 1 3 0 , 1 9 9 6 C H A U F F A IL L E , M .L .L .F .; Y A M A M O T O , M .; O O O N E P , V . e t a l. - A t (9 ;1 1 ) tra n s lo c a tio n in
